11-Step Total Synthesis of Araiosamines

Article abstract of DOI:10.1021/jacs.6b09701

A concise route to a small family of exotic marine alkaloids known as the araiosamines has been developed, and their absolute configuration has been assigned. The dense array of functionality, high polarity, and rich stereochemistry coupled with equilibrating topologies present an unusual challenge for chemical synthesis and an opportunity for innovation. Key steps involve the use of a new reagent for guanidine installation, a remarkably selective C-H functionalization, and a surprisingly simple final step that intersects a presumed biosynthetic intermediate. Synthetic araiosamines were shown to exhibit potency against Gram-positive and -negative bacteria despite a contrary report of no activity.

Full text of DOI:10.1021/jacs.6b09701

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Communication
11-Step Total Synthesis of Araiosamines
Maoqun Tian, Ming Yan, and Phil S. Baran
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 17 Oct 2016
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Journal of the American Chemical Society
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1-Step Total Synthesis of Araiosamines
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Maoqun Tian, Ming Yan, and Phil S. Baran
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Supporting Information Placeholder
5
ABSTRACT: A concise route to a small family of exotic marine
alkaloids known as the araiosamines has been developed and their
absolute configuration has been assigned. The dense array of
functionality, high polarity, and rich stereochemistry coupled with
equilibrating topologies present an unusual challenge for chemical
synthesis and an opportunity for innovation. Key steps involve the
use of a new reagent for guanidine installation, a remarkably se-
lective C–H functionalization, and a surprisingly simple final step
that intersects a presumed biosynthetic intermediate. Synthetic
araiosamines were shown to exhibit potency against gram positive
and negative bacteria despite a contrary report of no activity.
by the instability of indolylacetaldehyde derivatives.
Although variants of the cyclic core (e.g., 12 and 13)
were furnished stereoselectively via a Diels-Alder reac-
tion or an Achmatowicz rearrangement, such endeavors
were plagued by the extraneous functionalities associat-
ed with the ring-forming reactions.
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The marine environment is a constant source of exotic
and even mystifying new molecular architectures. In
1
2
011 the Ireland group reported the isolation of araiosa-
2
mines A-D (1-4, Figure 1A), remarkable structures en-
tangled by two guanidine units and decorated by three
bromoindole heterocycles. These highly polar species
feature six contiguous stereocenters and, in the case of 3
and 4, unique bicyclo[4.3.1] architectures. It is logical to
assume that 1-4 originate from the same biosynthetic
precursor, dubbed "pre-araiosamine" (5) in the isolation
2
report, followed by addition of water, methanol (2), N-
cyclization or Pictet-Spengler cyclization (4). Past expe-
rience in the area of guanidine-containing marine natural
product synthesis has taught us that much unique chem-
istry can be learned by pursuing concise routes to such
densely functionalized and practically challenging mole-
1
(b),3
cules.
This realization coupled with their captivating
structure fueled our endeavor towards araiosamines,
even though these alkaloids were reportedly devoid of
significant bioactivities. In this Communication, a short
pathway to araiosamines loosely modeled after biosyn-
thesis is presented leading to the assignment of their
absolute configuration and a new chemoselective rea-
gent for guanidine installation.
Initial forays toward the araiosamines were propelled
by the intriguing hypothesis that guanidinyl enamine (6)
could serve as a precursor to 5 via a dramatic linear tri-
merization event (Figure 1B). Generation of 6 through
condensation or ring-chain tautomerization (of the corre-
sponding 2-aminoimidazolidine) was examined, albeit
with little success. Attempts to trimerize 8, 9 or 10 were
thwarted by their predisposition to uncontrolled
polymerization. A stepwise approach through sequential
Mannich reactions with ester enolates forged the skele-
ton expediently. Unfortunately, the desired stereochemi-
cal outcome, in particular the C-3–C-5 stereotriad, was
untenable on acyclic systems–only epimeric derivatives
of 11 was obtained (see SI for an extensive summary).
With the failure of the linear trimerization strategy, ap-
proaches towards a bicyclic tautomer of 5, herein re-
ferred to as "cyclo-pre-ariosamine" 7, were pursued
based on stereocontrolled functionalizations of a pyri-
dine/piperidine core (cyclic logic, Figure 1B). Direct
construction of such a tris-indolyl-pyridinium (14)
through the Chichibabin pyridine synthesis was foiled
2
2
,4
Figure 1. (a) Putative biogenesis of araiosamines and (b) evolu-
tion of synthetic strategies
The combined lessons from these extensively explored
strategies led to a hybrid approach. Hemiaminal 15 was
targeted as a viable precursor to 5. It was postulated that
15 could be synthesized concisely via 16 through con-
7
trolled linear oligmerization of simple building blocks
while its rigid bicyclic structure would confer stereocon-
trol over the final guanidine installation, thereby com-
bining strategic elements of linear/cyclic approaches.
.
.Scheme 1 depicts the successful synthesis of the arai-
osamines, commencing with the preparation of car-
bamoylsulfone 18: 6-bromo-tryptophol (17, commer-
cially available from numerous suppliers or prepared in
8
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a
Scheme 1. Total synthesis of araiosamines
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NHR3
NHR3
2
.
NHBoc
CN
19
OH
1.IBX;
BocNH2
R2
CN
CN
PhSO Na
SO Ph LiHMDS
2
2
R1
R2
20
R1
R2
21
Br
Br
(92%; 1:1)
[gram scale]
R =6-bromo-indol-3-yl
(67%)
N
N
t
[
gram scale]
2'. BuNH
H
2
H
1
Conditions d.r. (C2)
4.
1
7
18
2
(48%; 46% rsm)
3. Schwartz's
6.
R =N-boc-6-bromo-indoly-3-yl
LHMDS
LHMDS/ZnCl
2
LHMDS/DMPU 1:9
NaHMDS
LDA
1:1
1:4
reagent
BocHN
NTFA
R3=Boc
(
78%)
[
gram scale]
TFAN
1:5
1:2
N
NH2 OH
NHR OH
3
N
NHR3
NH OH
R2
MeO2C
3
26
5. TFA
R HN
CO Me
CO2Me
2
2
23
4
CHO
CO Me
6
5
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R1
R1
25
R1
R1
R2
R2
(70%; d.r.=1:1)
gram scale]
R1
R1
R1
R1
R2
22
[
2
7
24
Br
Br
Br
Br
Br
Br
then
DDQ
HN
HO
HN
HN
H2N
8
. PPTS
HC(OMe)3;
DMP;
NH2OH
3
R N
N
HN
HN
9. SmI2
H2O
HN
NH OH
3
2
7. DIBAL
Br
N
HN
N
antiperi-
planar
N
4
CO2Me
2
5
HO
OH
(63%)
HN
29
HN
HN
Br
OMe
NR3
Br
OMe
R1
R1
R1
2
NR3
N
NR3
30
N
H
N
H
H
8
15 (36%, 3 steps)
SMe
NHR3
10. HgCl2,
R3HN
31
Br
R3
31
Br
R3
Br
Br
R3
R3
H
Br
H
H
Br
Br
HN N
N N
N N
H N
HN
HN
2
11. H O
H
N
2
7a
NH
NH
OH
HN
tauto.
90°C
PPTS
NH
NH
NH
HN
HN
HN
2
NH
HN HN
N
N
N
1
HN
HN
HN
HN
Br
HO
OH
OMe
Br
HN
Br
NR3
Br
NR3
N
H
N
H
N
H
N
H
araiosamine A; 1
-epi-araiosamine A; 36
Br
35
34
32 (53%, 2 steps)
1
NH
11'. TFA
-
H O
2
Br
Br
H
N
H
N
Br
Br
H
Br
Br
HN N
H2N
NH
NH
N
HN
Br
NH
HN
H
N
NH
N
N
H
NH
N
HN
H
HN
NH
HN
NH
NH
N
NH
N
H
H
NH
HN
HN
Br
Br
HN
Br
Br
HN HN
N
H
N
H
N
H
33, iminium
7, enamine
Br
"pre-araiosamine"; 5
araiosamine D; 4 (8%)
araiosamine C; 3 (81%)
a
Reagents and conditions: (1) 17 (1 equiv), IBX (1.5 equiv), MeCN, 82°C, then tert-butyl carbamate (1 equiv), sodium benzenesulfinate (1.1 equiv), THF/H
2
O/formic
Cl , 25°C
(1:3) 0°C to 25°C; (6) 26 (1 equiv), THF, 25°C then DDQ (1.5 equiv),
, -78°C (36%, over 3 steps); (8) PPTS (1 equiv), MeOH/HC(OMe) (2:1), 25°C; DMP (2 equiv), THF, 25°C then
OH•HCl (11 equiv), NaOAc (5.5 equiv), EtOH, 50°C (63%, one pot); (9) SmI , THF/H O (6:1), 25°C; (10) N,N′-Di-Boc-S-methylisothiourea (31) (2.4 equiv),
HgCl (2.9 equiv), DMF, 25°C (53%, 2 steps); (11’) TFA/CH Cl (1:1), (11) PPTS (4.4 equiv), MeCN/H O (1:2), 25 to 90°C (3, 81%; 4, 8%, one pot); IBX=2-
iodoxybenzoic acid, LiHMDS=lithium bis(trimethylsilyl) amide, Schwartz’s reagent=ZrCp (H)Cl, TFA=trifluoroacetic acid, DDQ=2,3-dichloro-5,6-dicyano-1,4-
benzoquinone, DIBAL=diisobutylaluminum hydride, PPTS=pyridinium p-toluenesulfonate, DMP=1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one
t
acid, 25°C (67%, one pot); (2) 19 (3 equiv), LiHMDS (3 equiv), THF, -78°C (92%, 1:1); (2’) MeOH/ BuNH
78%); (4) 23 (3 equiv), LiHMDS (4 equiv), THF, -78°C (70%, d.r.=1:1); (5) TFA/CH Cl
MeCN, 25°C; (7) DIBAL (ca. 3 equiv), CH Cl
NH
2
(10:1); (3) Schwartz’s reagent (2 equiv), CH
2
2
(
2
2
2
2
3
2
2
2
2
2
2
2
2
2 steps from 6-bromoindole) was oxidized to the corre-
sponding aldehyde which was subjected to a three-
component coupling with BocNH and PhSO Na to fur-
Subsequent aldol reaction between 22 and the lithium
enolate of 23 forged the entire carbon skeleton of arai-
osamines, albeit without stereocontrol as the desired
product, 24, was formed in equal amounts with its C-2
epimer. Extensive attempts to improve the diastereose-
lectivity met with little success as variations of nucleo-
philes (e.g., isopropyl ester or lithiated 19, see SI for
details) and bases or additions of chelating agents and
Lewis acids universally favored the undesired diastere-
omer. Nevertheless, the conciseness of the sequence still
allowed us to procure ample amounts of 24.
2
2
nish the stable acylimine precursor (18).
Mannich
reaction
of
lithiated
N-Boc-6-
bromoindolylacetonitrile (18) with the in situ derived
imine from 17 afforded the desired anti-adduct 21 (as-
signed by X-ray) alongside the syn-diastereomer 20
which could be easily funneled back to 21 upon epimer-
ization with BuNH . Reduction of the nitrile in 21 was
examined next. The use of conventional reductants such
as DIBAL led to low yields (ca. 20%) and substantial C-
epimerization, but hydrozirconation using Schwartz’s
reagent delivered ample amounts of the desired aldehyde
t
8b
2
Treatment of 24 with TFA unveiled the free amine,
setting the stage for the installation of the first guani-
dine. Several guanidinylation reagents were surveyed:
4
10
9
11
2
2 with minimal stereochemical erosion.
Goodman’s reagent failed to react with 25 even at ele-
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lithium aluminum hydride and sodium; various combi-
vated temperatures presumably owing to steric effects
12
1
while reaction with 31 only proceeded in the presence
nations of sodium borohydride and metal salts led to
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
of mercuric chloride, forming substantial amounts of
side products. Even N,N-bis-Boc-guanylpyrazole, was
debrominations (See SI). A combination of SmI and
2
13
19
H O was singularly successful: 29 was reduced to pri-
2
completely unreactive with 25. To address this problem,
N-Boc, N’-trifluoroacetyl-guanylpyrazole (26) was syn-
thesized; it was surmised that the TFA group would im-
part the carboximidamide moiety adequate reactivity to
engage hindered or electron deficient amines. Indeed, 26
exhibited considerable reactivity towards an assortment
of substrates (Table 1), including electron deficient ani-
lines (39a, 41) and drug molecules (39d). The bis-acyl
guandine product could be isolated as in the case of 40;
alternatively, the TFA group could be removed in the
mary amine 30 stereoselectively as the thermodynamic
product. The second guanidine was appended onto crude
30 using 31, yielding 32 and setting the stage for the
pivotal N-7a/C-1 cyclization.
Intriguingly, exposure of 32 to TFA did not elicit the
logically expected outcome. Instead, the resulting imini-
um 33a spontaneously tautomerized to enamine 7 (“cy-
clo-pre-araiosamine”) which failed to cyclize under var-
ious acidic media. Hydrolysis of 32 with aqueous PPTS
gave 34 whereupon activation (MsCl/pyridine) of the
hemiaminal also led to enamine formation. It was rea-
soned that the C-2 indole readily and reversibly engages
the iminium to shield the top face from N-7a cyclization
(vide supra). To surmount this vexing neighboring group
effect and the enamine dead-end, aqueous conditions
were selected that might encourage equilibration. To-
wards this end, 32 was first hydrolyzed to 34 at ambient
temperature; heating this mixture to 90°C removed the
Boc groups, thus liberating 35 which was found to exist
in equilibrium with araiosamine A (1) and 1-epi-
araiosamine A (36) through ring-chain tautomerization.
While isolated 1 reverted back to a tautomeric mixture
containing 35 and 36 over several hours, continued heat-
ing of this mixture yielded araiosamines C (3) and D (4)
through the intermediacy of “pre-araiosamine” (5), lend-
ing credence to the biosynthetic niche of this dihydroam-
inopyrimidine.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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7
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9
0
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2
3
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
same pot upon treatment with methanolic KHCO to
3
14
afford mono-acylguanidines. Reaction between 25 and
6 proceeded chemoselectively to yield the guanidinyla-
tion product (27). Subsequent treatment with DDQ in
2
1
5
the same pot enabled a “Yonemitsu-type” oxidation of
the C-6 indole to elicit a cyclization that occured with
1
6
complete chemo and stereoselectivity. Notably, two
other unprotected indoles were left unscathed during this
formal C–H functionalization process. The chemoselec-
tivity may be ascribed to steric hindrance at C-2 and the
electron-withdrawing ester group at C-4; the stereoselec-
tivity is most likely dictated by the C-5 stereocenter.
Table 1. Scope of the guanidinylation reaction
Reduction of crude 28 afforded hemiaminal 15 where
direct displacement of the C-3 hydroxyl would install
the final guanidine in the correct stereochemistry. How-
ever, as the C-2 indole resides in an antiperiplanar con-
Figure 2. Synthesis of (+)-araiosamine C (see SI for conditions)
Since the absolute configuration of these natural prod-
ucts was not known, the racemic path to 1, 3, and 4 was
adapted to answer this lingering question. As shown in
Figure 2, this could be easily achieved by utilizing
1
7
formation, anchimeric displacement prevailed when
nucleophilic substitutions were attempted on derivatives
1
8
of 15, leading to overall stereoretention (See SI).
A
reductive amination approach was thus conceived: the
hemiaminal 15 was converted into its N,O-acetal which
was immediately subjected to Dess-Martin oxidation;
direct reductive amination of the ensuing ketone with
ammonium salts was unsuccessful. Oxime 29 was thus
prepared in a single-flask sequence. As anticipated, re-
duction of the oxime in 29 was a highly challenging un-
dertaking: not only is the oxime moiety sterically en-
cumbered by two adjacent indole nuclei; other function-
alities such as the N,O-acetal or three aryl bromides are
conceivably more prone toward reduction. Indeed, the
oxime was unreactive towards strong reductants such as
2
0
Ellman’s auxiliary in the initial Mannich step. Subject-
ing imine 41 under similar conditions afforded a mixture
of four diastereomers (7:1:2:0.5) (see SI for reagents and
conditions) with the desired compound 42 being the ma-
jor product. Facile purification of this mixture was
achieved after selective removal of the sulfinamide un-
der acidic condition followed by the carbamoylation of
the primary amine, affording 21 in high enantiomeric
excess. (The absolute configuration was confirmed to be
S,S through X-ray). Elaboration of this enantioenriched
2
1 through the sequence allowed the synthesis of (+)-
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Page 4 of 5
araiosamine C (3) which was found to be the natural
enantiomer based on its optical rotation.
Financial support for this work was provided by NIH (GM-
118176) and the German Research Foundation (DFG)
postdoctoral fellowship to M.T.). We thank Dr. Julian
Shaw for efforts during early stages of investigation, Sire-
nas for biological assays, Dr. D.-H. Huang and Dr. L. Pas-
ternack for assistance with NMR spectroscopy, and Prof. A.
L. Rheingold and Dr. C. E. Moore for X-ray analysis.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
With ample supplies of araiosamines secured, their
biological activities were examined. Natural araiosa-
mines were reported to be inactive against zebra fish
embryos, Staphyloccus areus, and HIV infection. Cyto-
toxic assays of synthetic 1 (as a tautomeric mixture with
REFERENCES
3
5 and 36), 3 and 4 seem to attest further to their bereft
(1) For some reviews on marine alkaloids, see: (a) Blunt, J. W.;
Copp, B. R.; Keyzers, R. A.; Munro, M. H. G.; Prinsep, M. R.
Nat. Prod. Rep. 2016, 33, 382 and references therein. For
some reviews on guanidine alkaloid synthesese, see: Berlinck,
R. G. S.; Romminger, S. Nat. Prod. Rep. 2016, 33, 456 and
references therein.
therapeutic value—no significant activities were ob-
served (Table 2). Nevertheless, in a surprising turn, arai-
osamines exhibited considerable activities against both
gram-positive and gram-negative bacteria (compare to
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
1
axinellamine A), in stark contrast to the original report.
(2) Wei, X.; Henriksen, N. M.; Skalicky, J. J.; Harper, M. K.;
Cheatham, T. E., III; Ireland, C. M.; Van Wagoner, R. M. J.
Org. Chem. 2011, 76, 5515.
To date, scalable total syntheses have allowed us to iden-
tify inactive natural products with erroneously reported
2
2
3c
(
3) (a) O’Malley, D. P.; Li, K.; Maue, M.; Zografos, A. L.;
Baran, P. S. J. Am. Chem. Soc. 2007, 129, 4762. (b) Rodri-
guez, R. A.; Pan, C.-M.; Yabe, Y.; Kawamata, Y.; Eastgate,
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Rodriguez, R. A.; Steed, D. B.; Kawamata, Y.; Su, S.; Smith,
P. A.; Steed, T. C.; Romesberg, F. E.; Baran, P. S. J. Am.
Chem. Soc. 2014, 136, 15403. (d) Su, S.; Seiple, I. B.; Young,
I. S.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 16490. (e)
Seiple, I. B.; Su, S.; Young, I. S.; Nakamura, A.; Yamaguchi,
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T.; Köck, M.; Baran, P. S. J. Am. Chem. Soc. 2011, 133,
potency. This study, much akin to the axinellamines,
represents a rare case where natural products initially
reported to lack biological activities have surfaced as
antibacterial agents. Marine isolates like 1, 3 and 4 are
difficult to isolate or grow in a cell culture. To this end,
chemical synthesis is ideally suited to procure these al-
kaloids for future biomedical evaluations.
Table 2. cytotoxic and anti-bacterial profiles (MIC in µg/mL).
1
4710.
(
(
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The alternating indole-guanidine motifs present in 1-4,
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trimerization, has been constructed concisely. Aside
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polar and sensitive motifs, the differing topologies ac-
cessible through ring-chain tautomerization add an addi-
tional layer of complication to the retrosynthetic strate-
gy. Pivotal to the success of this endeavor was the evolu-
tion of a hybrid approach which capitalized on this in-
nate property, the invention of a powerful reagent for the
installation of mono-protected Boc-guanidines (Aldrich
catalog # ALD00592), and a remarkably chemo- and
stereoselective C–H functionalization. Finally, the anti-
bacterial activity of these structures is a welcome dis-
covery that will be the subject of continued study.
(
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(
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(
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dines, see: Looper, R. E.; Haussener, T. J.; Mack, J. B. C. J.
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures and
1
13
(15) Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1977, 42, 1213.
(16) For an elegant example of guanidine alkaloid synthesis via
chemoselective C-H amination, see: Fleming, J. J.; Du Bois,
J. J. Am. Chem. Soc. 2006, 128, 3926.
(17) This is clear from molecular models and an X-ray analysis of
a closely related derivative, see SI for details.
analytical data ( H and C NMR, MS) for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
(
18) Hallet, D. J.; Gerhard, U.; Goodacre, S. C.; Hitzel, L.; Sparey,
E-mail: pbaran@scripps.edu (P.S.B.).
Author contributions
T. J.; Thomas, S.; Rowley, M. J. Org. Chem. 2000, 65, 4984.
(19) Denis, J.-N.; Jolivalt, C. M.; Maurin, M. M. L.; Jeanty, M.
Preparation of novel bis-indolic derivatives antibacterial
drugs and a process for preparing them. PCT Int. Appl. WO
§
These authors contributed equally.
Notes
2
013014102 A1, Jan 31, 2013.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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(
20) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev.
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S. J. Am. Chem. Soc. 2016, 138, 9425. (b) Villaume, M. T.;
Sella, E.; Saul, G.; Borzilleri, R. M.; Fargnoli, J.; Johnston, K.
A.; Zhang, H.; Fereshteh, M. P.; Murali Dhar, T. G.; Baran, P.
S. ACS Cent. Sci. 2016, 2, 27.
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21) This result does not rule out the possibility that the non-
natural enantiomer accounts for the antibacterial activity.
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